Down's syndrome, the major cause of congenital mental retardation, is also the most common birth defect in man. It was traditionally called "mongolism", a name which has fallen from favor. In addition to the more modern name, Down's syndrome, this anomaly is often referred to as trisomy 21. Whereas "Down's syndrome" is used to describe those individuals who present certain clinical features, the term, trisomy 21, refers to the presumed chromosomal basis for these features. Over 90 percent of the individuals affected with Down's syndrome have an extra number 21 chromosome in their cells.
Trisomy 21 results from nondisjunction or failure of chromosomes to separate sometime during either division of meiosis or mitosis. Most Down's syndrome individuals have trisomy 21, and conversely, in individuals who carry a translocation involving chromosome 21, and in mosaics who have both trisomic and normal cells, the characteristics of the syndrome are seen.
The frequency of Down's syndrome births has been strongly correlated to advanced maternal age. However, there appear to be two types ("A" and "B") of Down's syndrome, only one of them correlated with maternal age. And nondisjunction in the father can lead to a trisomy 21 child. Evidently factors different from those identified with age may operate to give a Down's syndrome genotype.
Regardless of the occurrence of Down's syndrome births to young mothers, the strong statistical correlation between increased frequency of Down's syndrome births and advanced maternal age has been the conventional basis for predicting the risk of giving birth to an affected child. Recent reports, however, cast doubt upon this practice. Several researchers have found a decrease in frequency of all births to older women during the 1960 to 1975 period, but a concomitant decline in Down's syndrome was not found. Holmes (Holmes, L. B. Genetic Counseling for the Older Pregnant Woman; New Data and Questions. N England J Med 298, 1419-1421 (1978)), in his study for the Massachusetts Department of Public Health, stated that while women younger than 35 years old are having 90 percent of all infants, they are also having 65 to 80 percent of all Down's syndrome infants. In these infants, the syndrome is associated with trisomy 21 with the same high frequency as in children of older mothers. Thus, it appears that the observed increase in frequency of Down's syndrome births to young mothers reflects an increase in trisomy 21 or nondisjunction.
Resolution of the problems surrounding the etiology of Down's syndrome is difficult. Advancing maternal age is apparently only one condition that provides an environment conducive to nondisjunction. In particular, many studies suggest that the tendency toward nondisjunction may be inherited, though a gene specific for nondisjunction has not yet been found. The possibility that action of a specific gene results in nondisjunction would account for a small minority of total Down's syndrome births (Alfi, O. S., Chang, R., Azen, S. P. Evidence for Genetic Control of Nondisjunction in Man. Am J Hum Genet 32, 477-483 (1980)). Nonspecific chromosomal abnormalities have been shown to be associated with the nondisjunction phenomenon, though mechanisms of how they exert their effects have not been suggested. For counseling purposes, the presence of chromosomal abnormalities in the parents would certainly help in ascertaining the risk of giving birth to a trisomy 21 child. Routine chromosome analysis, however, would be expensive, difficult to interpret, and, therefore, is not ordinarily advocated.
While seeking the causes of trisomy 21, investigators have studied a variety of biochemical factors that might promote nondisjunction. Those studies have been motivated, in part, by the need for a better way to predict a propensity toward nondisjunction than by citing maternal age statistics or performing cumbersome chromosome analyses.
For example, Down's syndrome individuals' high susceptibility to infections, particularly respiratory infections, provided the basis for various immunological studies. (Rowe, M. J. III, Agranoff, B. W., Tourtellotte, W. W. Immunoelectrophoretic Study of Serum Proteins in Mongolism. Neurology 16, 714-719 (1966); Lange, C. F., Justice, P., Smith, G. F. Milk Precipitins in Mongolism. Res Commun Chem Pathol Pharmacol 7, 605-612 (1974); Gershwin, M. E., Crinella, F. M., Castles, J. J., Trent, J. K. T. Immunological Characteristics of Down's Syndrome. J Ment Defic Res 21, 237-247 (1977); Fekete, G.; Kulcsar, G., Dan, P., Nasz, I., Sculer, D., Dobos, M. Immumological and Virological Investigations in Down's Syndrome. Eur J Pediatr 138, 59-62 (1982); Jacobs, P. F., Burdash, N. M., Manos, J. P., Duncan, R. C. Immunologic Parameters in Down's syndrome. Ann Clin Lab Sci 8, 17-22 (1978)). It appears from these investigations that the immunological differences between Down's syndrome and normal groups are directly related to the syndrome and its genetic origin rather than to varying degrees of exposure to infections.
In 1971, Kerkay et al. (Kerkay, J., Zsako, S., Kaplan, A. R. Immunoelectrophoretic Patterns Associated with Mothers of Children Affected with G.sub.1 -trisomy (Down's syndrome). Am J Mental Deficiency 75, 729-732 (1971)) reported the presence of an extra precipitin arc in the gamma-A region of immunoelectrophoretic patterns in the sera of 46 of 48 mothers of trisomy 21 children. This same precipitin arc was found in only 10 of 48 age-matched control mothers. In a later article, Kerkay et al. (Kerkay, J., Zsako, S., Cotton, J. E., Kaplan, A. R. Biochemical and Genetic Variables Associated with Mothers of G.sub.1 -trisomy Affected Children. Acta Genet Med Gemellol 24, 239-244 (1975)) described the use of three variables--familial mental retardation, acrocentric chromosome association, and the presence of the extra precipitin line--as a tool of genetic counseling in assessing the potential risk for giving brith to trisomy 21 children.
The extra precipitin arc observed by Kerkay et al. indicates the presence of a protein. That this protein should be found more frequently in the sera of mothers of Down's syndrome children than in the sera of mothers of unaffected children is significant. Not only may the protein be tied to the etiology of trisomy 21, but it seems to be an indicator of a higher potential of bearing a Down's syndrome child.